Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma.

Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

Risk Assessment of the Door-In-Door-Out Process at Primary Stroke Centers for Patients With Acute Stroke Requiring Transfer to Comprehensive Stroke Centers.

Background Patients with acute stroke at non- or primary stroke centers (PSCs) are transferred to comprehensive stroke centers for advanced treatments that reduce disability but experience significant delays in treatment and increased adjusted mortality. This study reports the results of a proactive, systematic, risk assessment of the door-in-door-out process and its application to solution design. Methods and Results A learning collaborative (clinicians, patients, and caregivers) at 2 PSCs and 3 comprehensive stroke centers in Chicago, Illinois participated in a failure modes, effects, and criticality analysis to identify steps in the process; failures of each step, underlying causes; and to characterize each failure's frequency, impact, and safeguards using standardized scores to calculate risk priority and criticality numbers for ranking. Targets for solution design were selected among the highest-ranked failures. The failure modes, effects, and criticality analysis process map and risk table were completed during in-person and virtual sessions. Failure to detect severe stroke/large-vessel occlusion on arrival at the PSC is the highest-ranked failure and can lead to a 45-minute door-in-door-out delay caused by failure to obtain a head computed tomography and computed tomography angiogram together. Lower risk failures include communication problems and delays within the PSC team and across the PSC comprehensive stroke center and paramedic teams. Seven solution prototypes were iteratively designed and address 4 of the 10 highest-ranked failures. Conclusions The failure modes, effects, and criticality analysis identified and characterized previously unrecognized failures of the door-in-door-out process. Use of a risk-informed approach for solution design is novel for stroke and should mitigate or eliminate the failures.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

p68/DdX5 supports ß-catenin & RNAP II during androgen receptor mediated transcription in prostate cancer.

The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. ß-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear ß-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and ß-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and ß-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and ß-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and ß-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating ß-Catenin and AR transcriptional activity in PCa cells.

Flexible cortical control of task-specific muscle synergies.

Correlation structure in the activity of muscles across movements is often interpreted as evidence for low-level, hardwired constraints on upper-limb function. However, muscle synergies may also emerge from optimal strategies to achieve high-level task goals within a redundant control space. To distinguish these contrasting interpretations, we examined the structure of muscle variability during operation of a myoelectric interface in which task constraints were dissociated from natural limb biomechanics. We found that, with practice, human subjects learned to shape patterns of covariation between arbitrary pairs of hand and forearm muscles appropriately for elliptical targets whose orientation varied on a trial-by-trial basis. Thus, despite arriving at the same average location in the effector space, performance was improved by buffering variability into those dimensions that least impacted task success. Task modulation of beta-frequency intermuscular coherence indicated that differential recruitment of divergent corticospinal pathways contributed to positive correlations among muscles. However, this feedforward mechanism could not account for negative correlations observed in the presence of visual feedback. A second experiment revealed the development of fast, target-dependent visual responses consistent with "minimum intervention" control correcting predominantly task-relevant errors. Together, these mechanisms contribute to the dynamic emergence of task-specific muscle synergies appropriate for a wide range of abstract task goals.

Lesbians' constructions of depression.

Lesbians are a marginalized group of women living in a heteronormative society. This study describes lesbians' subjective experiences of depression, and identifies the ways that dominant and alternative discourses shaped their understandings of depression and sexuality. Twelve self-identified lesbians participated in up to three in-depth interviews conducted over a 9-month period. Thematic analysis led to themes that explicated their physical and emotional descriptions of depression; identified troubled interpersonal relationships as a primary source of depression; and discussed the means implemented to cope with depression, including taking medication, engaging in therapy, developing social support networks, and discovering their own spirituality. Depression and sexuality were understood within the framework of the dominant discourses of (1) medical model, (2) dysfunctional family, and (3) organized religion; and the alternative discourses of (1) lesbian identity, (2) alternative families, and (3) spirituality. Nurses in clinical practice can assist depressed lesbian clients by bolstering explorations of spirituality and the development of strong support networks within the lesbian and gay communities. Politically, institutionalized heteronormativity must be attacked at every level.

Providing psychiatric-mental health care for Native Americans: lessons learned by a non-Native American PMHNP.

Providing culturally sensitive psychiatric-mental health nursing care to Native Americans requires a unique set of understandings. Traditional tribal customs and beliefs, historical events of the past 500 years, and acculturation and enculturation have affected Native Americans' health and well-being. In 2004, I had the opportunity to practice as a psychiatric-mental health nurse practitioner with a Native American tribe in the southwestern United States. This article describes the lessons I learned while practicing on the reservation and suggests ways other non-Native American practitioners can best serve this population.

Effects of sexuality on lesbians' experiences of depression.

1. Lesbians are members of every racial, ethnic, and socioeconomic group. 2. Very little is known about depression in lesbians, and thus far, study findings are conflicting. However, depression in lesbians seems to be underpinned by relationship issues and levels of social support. 3. Caring for lesbian clients requires nurses to think holistically, understand their clients' sexuality within the context of their life experiences, and demonstrate respect and acceptance.